From dietary intake to phenotype: decoding mediator roles in pancreatic disease pathways

Dear Editor, Zhang et al[1] identified a link between dietary intake and the risk of pancreatic disorders. Mechanistically, certain foods may alter the pancreas microenvironment by regulating inflammatory responses, oxidative stress, or the gut microbiome (GM). However, experimental models and biological evidence that directly demonstrate the pathogenic or protective effects of certain food components are few. The study by Zhang et al also lacks a mediation analysis. We used the mediated Mendelian randomization (MR) design[2], intending to clarify the following three core questions: 1) Which dietary components have genetically proven causative influence on pancreatic diseases? 2) Are these causal effects mediated by measurable mediators? 3) The extent of the mediating impact and its biological implications. According to the TITAN Guidelines 2025, we certify that this paper did not use any artificial intelligence (Supplemental Digital Content Table S1, available at: https://links.lww.com/JS9/G652)[3]. Figure 1A depicts the technical path of our work. Methodological details can be found in Supplemental Digital Content Table S2, available at: https://links.lww.com/JS9/G653. Figure 1.: The causal relationship pathway of “diet-mediating factor-pancreatic disease”. A. The technical route of research. B. The network diagram shows the association between dietary preferences and the risk of pancreatic diseases. The scatter plot depicts the many categories of mediating factors connected to AP (C), CP (D), and PC (E) risk. Dot plots depict the network of causal associations between diet and AP (F), CP (G), and PC (H)-related mediating factors. Significant causal pathways for “diet-mediating factor-disease” in AP (I), CP (J), and PC (K). AP: acute pancreatitis; CP: chronic pancreatitis; PC: pancreatic cancer. The results of the two-sample MR analysis related to acute pancreatitis (AP), chronic pancreatitis (CP), and pancreatic cancer (PC) can be found in Supplemental Digital Content Table S3, available at: https://links.lww.com/JS9/G683, Supplemental Digital Content Table S4, available at: https://links.lww.com/JS9/G683, Supplemental Digital Content Table S5, available at: https://links.lww.com/JS9/G683. Specifically, nine dietary preferences were linked with the risk of AP, five with the risk of CP, and seven with the risk of pancreatic cancer (PC) (Fig. 1B). The second stage, two-sample MR analysis, revealed 7 GM traits, 43 immune cell phenotypes, three inflammatory markers, 95 metabolites, 30 lipids, and 111 proteins linked to AP (Fig. 1C). Similarly, 15 GM features, 49 immune cell phenotypes, five inflammatory variables, 75 metabolites, 21 lipids, and 132 proteins were linked to CP risk (Fig. 1D). Eleven GM features, 29 immune cell phenotypes, one inflammatory factor, 64 metabolites, six lipids, and 112 proteins were linked to PC risk (Fig. 1E). The third phase, two-sample MR analysis, identified causal relationships between nine food preferences and 69 mediating factors (AP, Fig. 1F), five dietary preferences and 47 mediating factors (CP, Fig. 1G), and seven dietary preferences and 53 mediating factors (PC, Fig. 1H). Mediating MR analysis revealed six statistically significant causal pathways for “diet-mediating factor-pancreatic disease” (Fig. 1I–K). To begin, red meat liking may raise the risk of AP by lowering the level of sphingomyelin (d34:1) in the bloodstream. Low levels of sphingomyelin may be associated with reduced cell membrane integrity and increased sensitivity to inflammatory damage. Consuming red meat may compromise the membrane integrity of pancreatic acinar cells and exacerbate inflammatory responses by disrupting sphingomyelin metabolism. Furthermore, chicken liking may raise the risk of AP by increasing the level of receptor tyrosine protein phosphatase H (PTPRH), which regulates cell adhesion, motility, and signal transduction. Its overexpression may disrupt normal cell–cell or cell–matrix interactions, impairing pancreatic tissue integrity and damage repair. Cauliflower-like may protect against CP by increasing the ratio of mannose to fructose and decreasing the ratio of glucose to mannose. Abnormal glucose metabolism ratios are closely linked to chronic inflammation and fibrosis. Mannose contains anti-inflammatory and immune-regulating properties. Cauliflower, a cruciferous vegetable rich in antioxidants and dietary fiber, may help slow the progression of pancreatic fibrosis and functional impairment by regulating glucose metabolism, reducing oxidative stress, and mitigating chronic inflammation. These two concurrent mediating pathways contribute to cauliflower’s long-term pancreatic-protecting effect. Whole milk liking may help to reduce PC risk by improving the adenosine monophosphate (AMP)-to-tyrosine ratio. AMP is a key indicator of cellular energy levels. Its proportional rise may reflect or generate cellular metabolic stress, slowing tumor cell proliferation. Tyrosine is an essential precursor for protein synthesis. The shift in this ratio may indicate that milk consumption alters the balance of energy metabolism and anabolism in tumor cells. Fatty fish consumption may raise the risk of PC by lowering the level of granulocyte colony-stimulating factor (G-CSF). G-CSF primarily stimulates the production and activation of neutrophils. Neutrophils in the tumor microenvironment can either promote or inhibit tumor growth. Low G-CSF levels may indicate impaired immune surveillance function or changes in a specific immunological milieu, which could allow malignancies to bypass the immune system. This finding implies that different types of fish or cooking methods may have varying impacts on PC risk by modulating certain immune factors. In conclusion, this study identified probable causal pathways by which unique food preferences may increase the risk of various pancreatic illnesses through specific blood metabolites or proteins. However, these pathways must be validated in separate cohorts, and their specific involvement in pancreatic cells or tissues should be defined by experimental research.